Case study: ocrelizumab to dimethyl fumarate switch

Will the adoption of an induction-maintenance treatment paradigm be the legacy that COVID-19 leaves behind in the MS treatment landscape?

Case study:

I am 38 years of age and have been on ocrelizumab for just over two years having had five courses to date. I had my last course in late May. I had two doses of Moderna’s mRNA COVID-19 vaccine in March and April and have just found out that I have no antibodies against the coronavirus. I work as a secondary school teacher and I am concerned about being exposed to the virus at school. In addition, my mother has psoriatic arthritis and is on methotrexate (12.5mg per week). I am anxious about exposing her to the virus. I have asked my neurologist if I can switch to dimethyl fumarate (Tecfidera). She has said yes. Any advice about the timing of the switch? 

Prof G’s opinion:

I have already done a general Newsletter on why you would switch from an anti-CD20 therapy and how you would do this (see ‘Switching from an anti-CD20: the why and the how’, 7th-Aug-2020). 

It seems that the main driver for this patient is vaccine readiness and safety. She is right to have concerns about not having sufficient vaccine immunity to protect her against being infected with SARS-CoV-2; in particular, the delta and delta-plus variants, which are partial immune escape variants. We have an increasing number of patients in our centre on ocrelizumab who have been double vaccinated and have developed COVID-19. Some of these patients have had severe diseases and needed hospital admission and sadly one of these patients succumbed to the disease.

This patient tells me she had an antibody test which shows that she has not made an antibody response to the Moderna mRNA COvid-19 vaccine. This now seems to be the norm in B-cell depleted patients on anti-CD20 therapies. Despite being antibody-negative she is likely to have some T-cell responses to the virus, which may be sufficient to protect her against symptomatic COVID-19, severe disease and death. However, there at present, there is no way for us to test her T-cell responses as none of the T-cell assays has been validated clinically and made available in the NHS. I note in other countries some private laboratories are offering T-cell assays. If you do have them please be careful how you interpret the results. Based on some publications I suspect they are not that sensitive. The latter is based on the observation that in several early studies anti-coronavirus antibody-positive pwMS don’t have T-cell responses, which shouldn’t happen. So-called IgG antibody responses require T-cell help, therefore by definition someone with an anti-vaccine antibody response has to have CD4+ T-follicular helper cell response and a general CD4+-T-helper response as well. This is why I don’t trust the results of these T-cell assays.

I don’t really know what to advise this person about her work. She is clearly vulnerable and will remain so until she is able to be vaccinated and has been shown to have a robust antibody response. But even then normal people in the general population who are vaccinated can get infected with the new and emerging strains of the virus.

In the UK close to 50% of recent deaths from COVID-19 have been in double-vaccinated people. The vast majority of these deaths have been in the over 50-year-olds so the fact she is in her 30’s may reassure her. I would suggest that if she decides to continue to teach she tries to maintain social distancing in the school, makes sure her teaching environment has adequate ventilation and stress to her pupils why it is important for them to do their regular lateral flow tests. She should continue to wear a mask and maintain hand hygiene. 

I would, however, suggest that she avoids close contact with her mother who will be at very high risk of complications of COVID-19 because of methotrexate therapy and her age.  

As the switch from ocrelizumab to dimethyl fumarate is not for evident disease activity this patient has time on her hands. I would recommend she misses her next ocrelizumab infusion in November and gets her peripheral B-cell counts checked and to only have the vaccine if her B-cell counts are above 10/mm3, which seems to be the level associated with positive antibody responses to the vaccine. Most people will have to wait longer than 6 months post-ocrelizumab before their B-cells reconstitute, i.e. somewhere in the order of 9-12 months. 

Once she has had the vaccine and has seroconverted she can then initiate dimethyl fumarate. Please note that the treatment effect of ocrelizumab lasts many months and reactivation of MS disease activity is unlikely.

What about DMF?  

How effective is DMF post-ocrelizumab? I don’t know as there are no trials that I am aware of that have specifically looked at DMF post-ocrelizumab. However, this strategy of using an anti-CD20 therapy as induction therapy and follow it with a safer maintenance therapy such as DMF or teriflunomide makes sense. This is what I call an induction-maintenance strategy and is likely to become standard practice in the future to derisk anti-CD20 therapies. It makes no sense to leave pwMS on an anti-CD20 therapy indefinitely, in particular older people, with the rising incidence of serious infections with time. I think the vaccine-readiness issue will focus our minds on derisking strategies such as this. 

In general, DMF is only a mild to moderate immunosuppressive therapy. This assessment is based on the five tests I apply when considering whether or not a drug is immunosuppressive.

1. Mode of action: DMF inhibits NF-κB (nuclear factor kappa B), which is one of the master transcription factors in controlling inflammation. You can’t be an NF-κB inhibitor and not be immunosuppressive.

2. Lymphopaenia: drugs that cause significant lymphopaenia tend to be immunosuppressive. Total lymphocyte counts drop on average by about 30% on DMF and about 15% of subjects lower their lymphocyte counts below 800/mm3 and 5% below 500/mm3. In addition, DMF has a greater impact on CD8+cells more than CD4+ cells, which may explain why there is a relatively large herpes zoster or shingles signal in DMF-treated patients. 

The following is the section on Zoster from the Tecfidera SmPC.

“Herpes zoster infections have been reported with Tecfidera use. In an ongoing long-term extension study, in which 1736 MS patients are treated with Tecfidera, approximately 5% experienced one or more events of herpes zoster, the majority of which were mild to moderate in severity. Most subjects, including those who experienced a serious herpes zoster infection, had lymphocyte counts above the lower limit of normal. Grade 2 and 3 lymphopenia prevailed in subjects with concurrent lymphocytopenia. In the post-marketing setting, most cases of herpes zoster infection were non-serious and resolved with treatment. Limited data is available on ALC in patients with herpes zoster infection in the post-marketing setting. However, when reported, most patients experienced grade 2 (< 0.8 × 109/L to 0.5 × 109/L) or grade 3 (<0.5 × 109/L to 0.2 × 109/L) lymphopenia (see section 4.4).”

3. Opportunistic infections: it is clear that there is a small opportunistic infection signal with DMF. It started with a few cases of PML and there has been a steady number of case reports of DMF-treated patients with different opportunistic infections, including cryptococcal meningitis. So after this patient starts on DMF they must think they are necessarily safe from infections she will still need to be vigilant. 

4. Vaccine responses: Vaccine responses to recall antigens (tetanus) and new antigens (meningococcus) were reasonable in DMF treated patients, but the response to the pneumococcal vaccine was variable. Differences in the response to both tetanus toxoid and pneumococcal serotype 3 polysaccharide antigen were less in MS patients on DMF compared to those on beta-interferon. Importantly there is no data on the effectiveness and safety of live vaccines in patients taking DMF. The SmPC in fact warns against live vaccines. 

“Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Tecfidera unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.”

5. Secondary malignancies: At present, there is no clear secondary malignancy signal on DMF. However, based on its mode of action and level of immunosuppression (relatively mild on average) a signal may take decades to emerge (known-unknown). An analogy is azathioprine monotherapy, a mild first-line immunosuppressive therapy, in which the secondary cancer risk (lymphoma) only emerges after 10 years of treatment. So again be vigilant particularly for skin cancers (squamous and basal cell carcinomas) and haematological malignancies which tend to be the sentinel cancers with long-term immunosuppression. 

Conclusions

So in conclusion, this patients decision to switch from ocrelizumab to a safer oral therapy to optimise her COVID-19 vaccine response and to derisk the long-term immunosuppression associated with anti-CD20 therapies makes biological sense and is backed up by a good scientific rationale. Will this be the beginning of the induction-maintenance treatment strategy switch I have been asking various pharmaceutical companies to test in the last few years? I suspect this will be the legacy that COVID-19 leaves behind, i.e. a safer environment for pwMS on long-term maintenance DMTs. 

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.